Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Summary of the safety profile
Diarrhoea (up to 52.6%), leukopenia (up to 45.8%), bacterial infections (up to 39.9%) and vomiting (up to 39.1%) were among the most common and/or serious adverse reactions associated with the administration of CellCept in combination with ciclosporin and corticosteroids. There is also evidence of a higher frequency of certain types of infections (see section 4.4).

Tabulated list of adverse reactions

The adverse reactions from clinical trials and post-marketing experience are listed in Table 1, by MedDRA system organ class (SOC) along with their frequencies. The corresponding frequency category for each adverse drug is based on the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000). Due to the large differences observed in the frequency of certain adverse reactions across the different transplant indications, the frequency is presented separately for renal, hepatic and cardiac transplant patients.

Table 1 Adverse reactions



Adverse reaction
(MedDRA)                        Renal            Hepatic          Cardiac transplant       transplant       transplant
System Organ Class
Frequency        Frequency        Frequency
Infections and infestations
Bacterial infections             Very Common      Very Common        Very Common Fungal infections                Common           Very Common        Very Common Protozoal infections             Uncommon         Uncommon           Uncommon Viral infections                 Very Common      Very Common        Very Common Neoplasms benign, malignant and unspecified (including cysts and polyps) Benign neoplasm of skin          Common           Common             Common Lymphoma                         Uncommon         Uncommon           Uncommon Lymphoproliferative disorder     Uncommon         Uncommon           Uncommon Neoplasm                         Common           Common             Common Skin cancer                      Common           Uncommon           Common Blood and lymphatic system disorders
Anemia                           Very Common      Very Common        Very Common Aplasia pure red cell            Uncommon         Uncommon           Uncommon Bone marrow failure              Uncommon         Uncommon           Uncommon Ecchymosis                       Common           Common             Very Common Leukocytosis                     Common           Very Common        Very Common Leukopenia                       Very Common      Very Common        Very Common Pancytopenia                     Common           Common             Uncommon Pseudolymphoma                   Uncommon         Uncommon           Common Thrombocytopenia                 Common           Very Common        Very Common Metabolism and nutrition disorders
Acidosis                         Common           Common             Very Common Hypercholesterolemia             Very Common      Common             Very Common Hyperglycemia                    Common           Very Common        Very Common Hyperkalemia                     Common           Very Common        Very Common Hyperlipidemia                   Common           Common             Very Common Hypocalcemia                     Common           Very Common        Common Hypokalemia                      Common           Very Common        Very Common Hypomagnesemia                   Common           Very Common        Very Common Hypophosphatemia                 Very Common      Very Common        Common Hyperuricaemia                   Common           Common             Very Common Gout                             Common           Common             Very Common Weight decreased                 Common           Common             Common Psychiatric disorders
Confusional state                Common           Very Common        Very Common Depression                       Common           Very Common        Very Common Insomnia                         Common           Very Common        Very Common Agitation                        Uncommon         Common             Very Common Anxiety                          Common           Very Common        Very Common Thinking abnormal                Uncommon         Common             Common 

Nervous system disorders
Dizziness                        Common           Very Common   Very Common Headache                         Very Common      Very Common   Very Common Hypertonia                       Common           Common        Very Common Paresthesia                      Common           Very Common   Very Common Somnolence                       Common           Common        Very Common Tremor                           Common           Very Common   Very Common Convulsion                       Common           Common        Common Dysgeusia                        Uncommon         Uncommon      Common Cardiac disorders
Tachycardia                      Common           Very Common   Very Common Vascular disorders
Hypertension                     Very Common      Very Common   Very Common Hypotension                      Common           Very Common   Very Common Lymphocele                       Uncommon         Uncommon      Uncommon Venous thrombosis                Common           Common        Common Vasodilatation                   Common           Common        Very Common Respiratory, thoracic and mediastinal disorders
Bronchiectasis                   Uncommon         Uncommon      Uncommon Cough                            Very Common      Very Common   Very Common Dyspnea                          Very Common      Very Common   Very Common Interstitial lung disease        Uncommon         Very Rare     Very Rare Pleural effusion                 Common           Very Common   Very Common Pulmonary fibrosis               Very Rare        Uncommon      Uncommon Gastrointestinal disorders
Abdominal distension             Common           Very Common   Common Abdominal pain                   Very Common      Very Common   Very Common Colitis                          Common           Common        Common Constipation                     Very Common      Very Common   Very Common Decreased appetite               Common           Very Common   Very Common Diarrhea                         Very Common      Very Common   Very Common Dyspepsia                        Very Common      Very Common   Very Common Esophagitis                      Common           Common        Common Eructation                       Uncommon         Uncommon      Common Flatulence                       Common           Very Common   Very Common Gastritis                        Common           Common        Common Gastrointestinal hemorrhage      Common           Common        Common Gastrointestinal ulcer           Common           Common        Common Gingival hyperplasia             Common           Common        Common Ileus                            Common           Common        Common Mouth ulceration                 Common           Common        Common Nausea                           Very Common      Very Common   Very Common Pancreatitis                     Uncommon         Common        Uncommon Stomatitis                       Common           Common        Common Vomiting                         Very Common      Very Common   Very Common Immune system disorders
Hypersenstivity                  Uncommon         Common        Common 
Hypogammaglobulinaemia            Uncommon                 Very Rare           Very Rare Hepatobiliary disorders
Blood alkaline phosphatase increased                         Common                   Common              Common Blood lactate dehydrogenase increased                         Common                   Uncommon            Very Common Hepatic enzyme increased          Common                   Very Common         Very Common Hepatitis                         Common                   Very Common         Uncommon Hyperbilirubinaemia               Common                   Very Common         Very Common Jaundice                          Uncommon                 Common              Common Skin and subcutaneous tissue disorders
Acne                              Common                   Common              Very Common Alopecia                          Common                   Common              Common Rash                              Common                   Very Common         Very Common Skin hypertrophy                  Common                   Common              Very Common Musculoskeletal and connective tissue disorders
Arthralgia                        Common                   Common              Very Common Muscular weakness                 Common                   Common              Very Common Renal and urinary disorders
Blood creatinine increased       Common              Very Common               Very Common Blood urea increased             Uncommon            Very Common               Very Common Hematuria                        Very Common         Common                    Common Renal impairment                 Common              Very Common               Very Common General disorders and administration site conditions
Asthenia                         Very Common         Very Common               Very Common Chills                           Common              Very Common               Very Common Oedema                           Very Common         Very Common               Very Common Hernia                           Common              Very Common               Very Common Malaise                          Common              Common                    Common Pain                             Common              Very Common               Very Common Pyrexia                          Very Common         Very Common               Very Common De novo purine synthesis         Uncommon            Uncommon                  Uncommon inhibitors associated acute inflammatory syndrome


Description of selected adverse reactions
Malignancies
Patients receiving immunosuppressive regimens involving combinations of medicinal products, including CellCept, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.4). Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data.
Hepatic transplant patients were followed for at least 1 year, but less than 3 years.

Infections
All patients treated with immunosuppressants are at increased risk of bacterial, viral and fungal infections (some of which may lead to a fatal outcome), including those caused by opportunistic agents and latent viral reactivation. The risk increases with total immunosuppressive load (see section 4.4). The most serious infections were sepsis, peritonitis, meningitis, endocarditis, tuberculosis and atypical mycobacterial infection. The most common opportunistic infections in patients receiving 
CellCept (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials in renal, cardiac and hepatic transplant patients followed for at least 1 year were candida mucocutaneous, CMV viraemia/syndrome and Herpes simplex. The proportion of patients with CMV viraemia/syndrome was 13.5%. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including CellCept.

Blood and lymphatic disorders
Cytopenias, including leukopenia, anemia, thrombocytopenia and pancytopenia, are known risks associated with mycophenolate mofetil and may lead or contribute to the occurrence of infections and hemorrhages (see section 4.4). Agranulocytosis and neutropenia have been reported; therefore, regular monitoring of patients taking CellCept is advised (see section 4.4). There have been reports of aplastic anaemia and bone marrow failure in patients treated with CellCept, some of which have been fatal.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with CellCept (see section 4.4).
Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with CellCept. These changes are not associated with impaired neutrophil function. These changes may suggest a ‘left shift’ in the maturity of neutrophils in haematological investigations, which may be mistakenly interpreted as a sign of infection in immunosuppressed patients such as those that receive CellCept.

Gastrointestinal disorders
The most serious gastrointestinal disorders were ulceration and hemorrhage which are known risks associated with mycophenolate mofetil. Mouth, esophageal, gastric, duodenal, and intestinal ulcers often complicated by hemorrhage, as well as hematemesis, melena, and hemorrhagic forms of gastritis and colitis were commonly reported during the pivotal clinical trials. The most common gastrointestinal disorders, however, were diarrhoea, nausea and vomiting. Endoscopic investigation of patients with CellCept-related diarrhoea have revealed isolated cases of intestinal villous atrophy (see section 4.4).

Hypersensitivity
Hypersensitivity reactions, including angioneurotic oedema and anaphylactic reaction, have been reported.

Pregnancy, puerperium and perinatal conditions
Cases of spontaneous abortion have been reported in patients exposed to mycophenolate mofetil, mainly in the first trimester, see section 4.6.

Congenital disorders
Congenital malformations have been observed post-marketing in children of patients exposed to CellCept in combination with other immunosuppressants, see section 4.6.

Respiratory, thoracic and mediastinal disorders
There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with CellCept in combination with other immunosuppressants, some of which have been fatal. There have also been reports of bronchiectasis in children and adults.

Immune system disorders
Hypogammaglobulinaemia has been reported in patients receiving CellCept in combination with other immunosuppressants.



General disorders and administration site conditions
Oedema, including peripheral, face and scrotal oedema, was reported very commonly during the pivotal trials. Musculoskeletal pain such as myalgia, and neck and back pain were also very commonly reported.

De novo purine synthesis inhibitors associated acute inflammatory syndrome has been described from post-marketing experience as a paradoxical proinflammatory reaction associated with mycophenolate mofetil and mycophenolic acid, characterised by fever, arthralgia, arthritis, muscle pain and elevated inflammatory markers. Literature case reports showed rapid improvement following discontinuation of the medicinal product.

Special populations

Paediatric population
The type and frequency of adverse reactions in a clinical study, which recruited 92 paediatric patients aged 2 to 18 years who were given 600 mg/m2 mycophenolate mofetil orally twice daily, were generally similar to those observed in adult patients given 1 g CellCept twice daily. However, the following treatment-related adverse events were more frequent in the paediatric population, particularly in children under 6 years of age, when compared to adults: diarrhoea, sepsis, leucopenia, anaemia and infection.

Elderly
Elderly patients (≥ 65 years) may generally be at increased risk of adverse reactions due to immunosuppression. Elderly patients receiving CellCept as part of a combination immunosuppressive regimen may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared to younger individuals.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form /https://sideeffects.health.gov.il